RevDate: 2025-12-11

Zhang L, Li L, Cao P, et al (2025)

An Efficient Transfer Learning With Prompt Learning for Brain Disorders Diagnosis.

IEEE journal of biomedical and health informatics, PP: [Epub ahead of print].

The limited availability of training data significantly restricts the performance of deep supervised models for brain disease diagnosis. It is crucial to develop a learning framework through cross-disease transfer learning that can extract more information from the limited data. To address this challenge, we concentrate on prompt learning and endeavor to extend its application to the brain networks. Specifically, we propose a novel prompt learning framework called BPformer, which integrates knowledge transferred across diseases via specific prompts while keeping the original architecture of BPformer unchanged. The specific prompts incorporate 1) a mask prompt to determine whether the edges are noisy or discriminating, 2) disorder prompts for modeling consistent and disorder-specific knowledge, and 3) adaptive instance-level prompts to account for inter-individual variations. We evaluate BPformer on the private center Nanjing Medical University dataset, the public Autism Brain Imaging Data Exchange dataset, and the public Alzheimer's Disease Neuroimaging Initiative dataset. We demonstrate the effectiveness of the proposed model across various disease classification tasks, including major depressive disorder, bipolar disorder, alzheimer's disease, and autism spectrum disorder diagnoses. In addition, the proposed method enables disease interpretability and subtype analysis, empowering physicians to provide patients with more accurate and fine-grained treatment plans.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Mohanty R, Wheatley S, Chiotis K, et al (2025)

Distinct cerebrovascular pathways underlying Alzheimer's disease-related neurodegeneration.

Acta neuropathologica, 150(1):64.

The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = - 20, 95% CI - 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < - 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = - 0.2, 95% CI - 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.

RevDate: 2025-12-11

Taylor LW, Simzer EM, Young LFP, et al (2025)

Confirmation of p-tau Ser356's association with Alzheimer's disease pathology and lowering in response to WZ4003 treatment in brain slice cultures. Reply to: "Phospho-tau Ser356 is mostly confined to pre-NFT neurons in Alzheimer's pathology".

Acta neuropathologica, 150(1):63.

RevDate: 2025-12-11

Begines P, Fernández-Bolaños JG, Ó López (2025)

An updated patent review of acetylcholinesterase inhibitors for the treatment of alzheimer's disease (2021 - present).

Expert opinion on therapeutic patents [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex and not fully elucidated etiology. An exponential rise in its incidence underscores the urgent need for effective therapeutic strategies. AD imposes a significant economic burden on public healthcare systems and on patient's families.

AREAS COVERED: This manuscript focuses on the review of potent acetylcholinesterase (AChE) inhibitors, either through chemical synthesis or isolation from natural sources, aimed at restoring acetylcholine levels. Most of the compounds discussed act as multitarget agents and are categorized into four groups: drug derivatives (9 patents), heterocyclic scaffolds (16 patents), natural products from plant extracts (12 patents), and synthetic compounds inspired by natural templates (18 patents).

EXPERT OPINION: AChE inhibition remains a compelling target in AD drug design, as it enhances acetylcholine levels and can alleviate cognitive decline. Furthermore, inhibitors that interact with the peripheral anionic site (PAS) of AChE may reduce β-amyloid self-aggregation, thereby preventing the deposition of neurotoxic peptides in the brain. However, targeting AChE alone is insufficient for the development of effective therapeutics. A multitarget approach, combining AChE inhibition with pharmacophores addressing β-amyloid aggregation, neuroinflammation, oxidative stress, and other pathological hallmarks, holds greater promise for the development of more efficient anti-Alzheimer's agents.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Li W, Huang W, Zhou P, et al (2025)

Sporoderm-removed ganoderma lucidum spore powder (S-GLSP) alleviates neuroinflammation injury by regulating microglial polarization through inhibition of NLRP3 inflammasome activation.

Frontiers in pharmacology, 16:1690192.

INTRODUCTION: Sporoderm-Removed Ganoderma lucidum Spore Powder (S-GLSP), derived from the spores of the medically valued fungus Ganoderma lucidum, exhibits diverse pharmacological activities and shows considerable potential in the treatment of Alzheimer's disease (AD). However, its underlying mechanisms of action remain incompletely elucidated. This study aims to investigate the protective effects of S-GLSP against AD and to explore the molecular mechanisms involved.

MATERIALS AND METHODS: The chemical profile of S-GLSP extract was characterized using LC-MS/MS. Alzheimer's disease models were established both in vivo and in vitro: a rat model was induced by D-galactose combined with intracerebroventricular injection of Aβ, while a cellular model was stimulated with LPS. The neuroprotective effects of S-GLSP were assessed through behavioral tests and hematoxylin-eosin (HE) staining. Immunofluorescence staining, Western blot (WB), RT-qPCR, and ELISA were employed to evaluate microglial polarization and NLRP3 inflammasome activation. Cell viability was measured using MTT and EdU assays. Finally, NLRP3 knockdown was performed to verify whether S-GLSP modulates microglial polarization via regulation of the NLRP3 inflammasome.

RESULTS: A total of 42 chemical compounds were identified in S-GLSP, including flavonoids, alkaloids, terpenoids, saccharides, phenolics, fatty acids, nucleosides, amino acids, and other. S-GLSP treatment alleviated neuronal damage, improved learning and memory deficits, and reduced the expression of phosphorylated tau (p-tau) in AD model rats. Further experiments in vitro and in vivo showed that S-GLSP downregulated M1 phenotypic markers (CD86, iNOS, TNF-α) and upregulated M2 markers (CD206, Arg-1, IL-10). Moreover, S-GLSP inhibited NLRP3 inflammasome activation and regulated the secretion of IL-1β and IL-18, effects that were consistent with those observed following NLRP3 knockdown.

CONCLUSION: Our findings demonstrate that S-GLSP alleviates Alzheimer's disease pathology by inhibiting NLRP3 inflammasome activation, promoting a shift in microglial polarization from the M1 to the M2 phenotype, and modulating the release of inflammatory cytokines. This study provides novel mechanistic insights into the therapeutic potential of S-GLSP for AD.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Monteiro R, Dunn JT, Rodriguez G, et al (2025)

Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.

Research square pii:rs.3.rs-8031077.

Alzheimer's disease (AD) is frequently accompanied by neuropsychiatric symptoms (NPS), among which apathy, one of the most prevalent and burdensome, accelerates cognitive decline and disease progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing of AD subjects revealed abnormal immune gene expression uniquely associated with apathy. In this study, we investigated whether these changes are also linked to apathy-like behavior in 5xFAD mice, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies these behaviors. We first validated the expression of apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-month-old 5xFAD mice using RT-qPCR. Separate cohorts of similarly aged 5xFAD and WT mice then received SB290157 and/or methylphenidate for two weeks. Results indicate that increased immune-related genes, including Tyrobp, C3 , C3ar , C1qa , C1qb , and C1qc expression, were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment significantly improved nest-building behavior, reduced C3 and C3ar protein expression, as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Pandey P, Rajput S, Gaur T, et al (2025)

Animal models in human surgery and implant innovation: ethical considerations and scientific advancements.

Annals of medicine and surgery (2012), 87(12):8291-8303.

The main aim of biological research is to bridge the gap between preclinical findings and clinical applications so that human health can be improved. Animal models are beneficial in replicating disease mechanisms, facilitating diagnosis, and assessing treatment efficacy for any disease. They play a vital role in drug discovery, toxicological assessments, dosage determination, and the evaluation of side effects, all while adhering to the ethical guidelines. These models are effectively used to treat a wide range of human diseases, including autoimmune disorders, rheumatoid arthritis, epilepsy, Alzheimer's disease, cardiovascular conditions, atherosclerosis, severe acute respiratory syndrome/Coronavirus disease 2019 (SARS/COVID-19), and diabetes. In disease modeling, they significantly contribute to drug development, medical device testing, tissue engineering, wound healing, and bone and cartilage regeneration. One cannot deny the fact that there are major significances of small and large animal models in scientific studies, apart from various advantages and challenges. Animal Models play an essential role in pharmaceutical research, biomedical research, genome editing, transgenic studies, and surgical applications. These models enable scientists and researchers to perform experiments that would be ethically or practically impossible in humans. In recent years, various animal species have been widely used to study health problems, including the 2019 Coronavirus pandemic, diabetes, and obesity. Mice, pigs, rabbits, rats, murine, primate, porcine, and aquatic models have played a crucial role in understanding the neurological, behavioral, cardiovascular, and oncological disorders while contributing to the development of innovative therapeutic approaches for their treatment. The studies in which pain is inflicted on animals must follow strict ethical standards. Whereas research involving painless animal death is often more accepted because of the fact that animals have limited awareness of their future. This review highlights the use of animal models in indispensable contributions to modern medicine and underscores their relevance in disease research, treatment development, and ethical considerations in experimental studies and their scientific advancements.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Li X, Gao W, Ye Q, et al (2025)

The Role and Therapeutic Potential of the cGAS-STING Signaling Pathway in Alzheimer's Disease.

Brain and behavior, 15(12):e71130.

PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, posing a significant challenge to global public health. As a core signaling pathway in the mammalian innate immune system, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in maintaining intracellular homeostasis. This review aims to systematically elucidate the role and therapeutic potential of the cGAS-STING signaling pathway in AD, focusing on its involvement in key pathological processes and its relevance to AD risk factors.

METHOD: Through literature search, we summarized the molecular mechanisms of the cGAS-STING pathway and its dysregulation in AD, emphasizing the integrated evidence linking cGAS-STING to neuroinflammation, autophagy impairment, and neuronal death, as well as its interactions with aging, obesity, cardiovascular disease, and diabetes.

FINDINGS: The cGAS-STING pathway is critically involved in AD pathogenesis, contributing to neuroinflammation, defective autophagy, and neuronal loss. Its activation is associated with multiple AD risk factors, suggesting a broad influence on disease progression. Pharmacological inhibition of cGAS-STING shows promise in attenuating these pathological features in preclinical models.

CONCLUSION: The cGAS-STING signaling pathway plays a central regulatory role in the central nervous system, and its dysregulation promotes neuroinflammation and is closely associated with AD. This pathway forms a vicious cycle by integrating multiple pathological signals, including mitochondrial dysfunction and endoplasmic reticulum stress. Small-molecule inhibitors and natural products targeting this pathway have demonstrated significant efficacy in preclinical studies, providing a basis for developing disease-modifying therapies for AD. Future efforts should focus on multi-target combination strategies (e.g., STING inhibitors co-administered with Aβ/tau drugs) and dynamically deciphering pathway alterations across AD stages to advance personalized treatment approaches.

RevDate: 2025-12-11
CmpDate: 2025-12-11

O'Donnell AJ, Zhao X, Parr A, et al (2025)

Early Outcomes of Lecanemab for Alzheimer's Disease in the Veterans Health Administration.

Journal of clinical medicine, 14(23): pii:jcm14238277.

Background/Objectives: While lecanemab (Leqembi) and several amyloid targeting therapies were approved for Alzheimer's disease, questions remain on real-world implementation, safety, and effectiveness. The objective of this study was to describe the uptake and early outcomes of Veterans initiating lecanemab. Methods: This retrospective cohort study included Veterans who initiated lecanemab in the Veteran's Health Administration (VHA) between October 2023 and July 2024. Treatment persistence and monitoring, change in Montreal Cognitive Assessment (MoCA) score, incidence of adverse events, including amyloid-related imaging abnormalities (ARIA), and healthcare utilization were analyzed at 7 months. Results: Overall, 32 Veterans (mean [SD] age 75.3 [6.0] years, 100% male, 97% white, 84% urban dwelling) initiated lecanemab. Seventeen patients (53%) had mild cognitive impairment, 15 (47%) had mild dementia; mean baseline MoCA score was 21.3 (SD 3.4). At 7 months following treatment initiation, we assessed process, safety, and effectiveness outcomes. Process outcomes: In all, 25 patients (78%) were persistent with treatment. Safety outcomes: Three patients (9%) experienced a stroke, and 7 (22%) experienced ARIA. Effectiveness outcomes: Only 12 (38%) patients had a MoCA completed by 7 months, and the mean change in MoCA was 0.0 (SD 3.7, p = 1.0). A follow-up amyloid positron emission tomography (PET) scan was completed by 9 (28%) patients, and 5 had reductions in amyloid. Conclusions: Initial observations in a small VHA cohort suggest that uptake of lecanemab was limited, and the finding that nearly 30% of patients experienced ARIA or stroke within 7 months of initiation underscores the importance of monitoring the lecanemab safety and effectiveness long-term. These early findings should be interpreted cautiously given the limited sample size and very limited follow-up MoCA data.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Vieira RC, Nascimento LA, Nascimento AA, et al (2025)

NCIVISION: A Siamese Neural Network for Molecular Similarity Prediction MEP and RDG Images.

Molecules (Basel, Switzerland), 30(23): pii:molecules30234589.

Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer's disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Tsopka IC, Pontiki E, Sigala I, et al (2025)

Design, Synthesis, Biological Evaluation, and In Silico Studies of Novel Multitarget Cinnamic Acid Hybrids.

Molecules (Basel, Switzerland), 30(23): pii:molecules30234582.

Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer's disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid-nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids 5a-i, 6a-i, 9a-i, and 11 were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids 6a-i, 9a-i, and 11 that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound 9a is a promising multitarget agent, exhibiting the lowest IC50 for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound 9e demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX-LOX inhibitor. Additionally, compound 6i exhibited the strongest cytotoxic activity among the tested compounds, with EC50 values ranging from 36 to 45 μM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Kimble R, OM Shannon (2025)

Can Beetroot (Beta vulgaris) Support Brain Health? A Perspective Review on Alzheimer's Disease.

Nutrients, 17(23): pii:nu17233790.

Alzheimer's disease (AD), the leading cause of dementia, has limited treatment options despite extensive pharmacological research. This has increased interest in dietary strategies that act across multiple pathological mechanisms. Beetroot (Beta vulgaris), known for its cardiovascular and metabolic benefits, contains a distinctive combination of bioactive compounds including inorganic nitrate, betalains, and polyphenols. Together these constituents influence vascular function, oxidative stress, mitochondrial efficiency, inflammation, and the microbiota. Previous reviews have typically focused on dietary nitrate in dementia prevention or have examined nitrate and betalains separately. In contrast, this review synthesises evidence on beetroot as a combined neuroprotective food. Preclinical data indicate that beetroot and its key constituents enhance antioxidant defences, support neuronal bioenergetics, and modulate cholinergic and inflammatory pathways. Human studies further suggest that nitrate-rich beetroot can improve cerebral blood flow and vascular responsiveness, and that higher intakes of plant-derived nitrate are associated with reduced cognitive decline. However, findings are inconsistent, most trials are small and short in duration, and research directly involving people with AD is scarce. By integrating vascular, antioxidant, and microbiome perspectives, this review identifies beetroot as a promising yet underexplored dietary candidate for AD management. Further mechanistic studies and multidomain approaches combining metagenomics, biomarkers, neuroimaging, and cognitive outcomes are needed.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Calzoni E, Cusumano G, Bertoldi A, et al (2025)

Rhubarb-Derived Extracellular Vesicles Mitigate Oxidative Stress and Metabolic Dysfunction in an Alzheimer's Cellular Model.

Nutrients, 17(23): pii:nu17233771.

Background/Objectives: Extracellular vesicles derived from edible plants have emerged as bioactive nanostructures with potential therapeutic and nutraceutical properties and are currently being investigated as natural carriers for the treatment of oxidative stress-induced damage and oxidative stress-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). Recent studies suggest that PDEVs exhibit high stability within the gastrointestinal tract and selective tissue-targeting abilities, facilitating the efficient delivery of bioactive molecules. Methods: This study investigates the antioxidant effects of Rheum rhabarbarum-derived EVs by assessing the antioxidant activity through different in vitro assays and their effects on oxidative stress and energy metabolism in the cellular model of Alzheimer's disease. Results: Rhubarb-derived EVs showed measurable antioxidant capacity in chemical assays and were non-toxic under the tested conditions. Treatment reduced intracellular ROS levels and modulated oxidative stress-related proteins, suggesting a potential protective effect against oxidative damage. Moreover, metabolic analysis revealed a decrease in glycolytic activity, indicating a potential restoration of cellular bioenergetic homeostasis. Conclusions: These results provide preliminary evidence supporting the nutraceutical interest of rhubarb-derived EVs in counteracting oxidative stress, while further studies will be needed to confirm their biological relevance and therapeutic potential.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Brehar FM, Costea D, Tataru CP, et al (2025)

The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration.

International journal of molecular sciences, 26(23): pii:ijms262311536.

The way in which Aquaporin-4 (AQP4) is localized on the astrocytes' surface-i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels-represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood-brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity-a loss in the organization of AQP4 channels to the perivascular membrane-is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4-such as dystrophin-syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators-and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood-brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the "fluidic connectome", and highlight its importance in maintaining overall brain health across disease states.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Ishikawa K, Fujikawa R, Okita K, et al (2025)

Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?.

International journal of molecular sciences, 26(23): pii:ijms262311494.

With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammation and impaired clearance of cellular debris, processes that are primarily regulated by microglia, the resident immune cells of the brain. As aging progresses, microglia exhibit reduced surveillance and motility, diminished phagocytic efficiency, and transition into a proinflammatory, hyperresponsive state. Such maladaptive microglia contribute to synaptic loss, white matter deterioration, and the spread of neurodegenerative pathology. Conversely, single-cell transcriptomic studies have identified distinct microglial subsets, including CD11c[+] microglia, which show upregulation of lysosomal and lipid metabolism pathways, enhanced debris clearance, and elevated neurotrophic factor expression. These features suggest that certain microglial populations adopt protective or adaptive phenotypes that preserve neural integrity. However, under chronic inflammation or pathological conditions, even protective microglia may become inflammation-promoting. This review summarizes current evidence on microglial changes in aging, frailty, and neurodegeneration, emphasizing their dual roles and discussing strategies that modulate microglial function to maintain brain health and prevent or treat frailty and age-related diseases.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Muzaffar S, Tyagi A, S Pugazhenthi (2025)

Therapeutic Potential of Irisin in Neurodegenerative Diseases.

International journal of molecular sciences, 26(23): pii:ijms262311348.

Irisin is a myokine secreted by muscle in response to exercise. It is derived from a transmembrane protein called fibronectin type III domain-containing protein 5 (FNDC5). The Fndc5 gene is expressed in several tissues, including skeletal muscle, brain, adipose tissue, heart, kidney, and lung. Irisin is cleaved from FNDC5 protein by the enzyme furin and released into circulation. In addition to exercise, several drugs have been shown to increase the production of irisin. Administration of exogenous irisin mimics the beneficial actions of exercise. Irisin can cross the blood-brain barrier and exert neuroprotective actions in the brain. It has been shown to reverse Alzheimer's pathologies in clinical and animal studies. Irisin also exerts protective effects against obesity, diabetes, and cardiovascular disease, diseases that often coexist with aging AD patients. Multiple approaches have been taken to suggest that exercise may act through irisin. Studies have provided direct evidence linking the two using Fndc5 gene deletion and irisin antibodies. Irisin binds to αVβ1/β5 integrins to mediate the activation of integrin-FAK pathways. While exercise as a lifestyle modification for healthy aging is well recognized, it may present limitations in some aging populations, especially those with disease conditions, including Parkinson's disease. Administration of exogenous irisin or small molecules that increase the expression of endogenous irisin or facilitate its actions are some alternate approaches that can mimic the beneficial actions of exercise. This review discusses the therapeutic potential of irisin in the treatment of neurodegenerative and other aging-associated diseases.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Adamski P, Szeleszczuk Ł, Gackowski M, et al (2025)

Creatine and Taurine as Novel Competitive Inhibitors of Acetylcholinesterase: A Biochemical Basis for Nutritional Modulation of Brain Function.

International journal of molecular sciences, 26(23): pii:ijms262311309.

Acetylcholinesterase (AChE) is a key enzyme responsible for terminating cholinergic neurotransmission by hydrolyzing acetylcholine. While clinically approved AChE inhibitors such as donepezil, rivastigmine, and galantamine are used in the symptomatic treatment of Alzheimer's disease and related dementias, little is known about the modulatory effects of common dietary compounds on AChE activity. In this study, we investigated the influence of creatine (CR) and taurine (TA)-two widely consumed nutritional supplements with reported neuroprotective and cognitive-enhancing properties-on AChE. Enzyme kinetics were evaluated using a modified Ellman's method, and Lineweaver-Burk analyses revealed that both CR and TA act as competitive inhibitors. Calculated parameters (Km, Vmax), inhibition constants (Ki), and half maximal inhibitory concentrations (IC50) consistently indicated stronger potency for CR (IC50 = 0.0056 ± 0.00018 mM) compared to TA (IC50 = 0.0097 ± 0.00035 mM). To complement the experimental data, molecular docking was performed using two crystal structures of human AChE. Docking confirmed that both ligands preferentially occupy the active-site region in a manner consistent with competitive inhibition, with CR showing more favorable binding scores than TA. Although markedly weaker than clinical drugs, these findings provide the first biochemical and in silico evidence that CR and TA directly interact with AChE, suggesting subtle cholinergic modulation relevant to cognitive function and neuroprotection.

RevDate: 2025-12-10

Mi F, Li H, Pan D, et al (2025)

Effect of organismal rhythmic activity on Aβ clearance by the glymphatic system.

European journal of medical research pii:10.1186/s40001-025-03646-5 [Epub ahead of print].

Abnormal deposition of β-amyloid (Aβ) is a significant pathological feature of neurodegenerative diseases, particularly Alzheimer's disease (AD). The glymphatic system (GS) plays a crucial role in Aβ clearance. Various rhythmic activities of the organism dynamically influence Aβ clearance by modulating GS function. In this paper, we systematically review the mechanisms linking cardiovascular rhythms, respiratory rhythms, neural rhythms, circadian rhythms, and exercise patterns to Aβ clearance via the GS. Cardiovascular rhythms affect cerebral perfusion pressure and vascular pulsation to regulate GS transport efficiency; respiratory rhythms modulate intracranial pressure and cerebrospinal fluid (CSF) circulation through thoracic pressure variations; neural rhythms (including delta waves during non-rapid eye movement (NREM) sleep and neurovascular coupling) synchronize neuro-glial-vascular interactions to enhance GS clearance. Circadian rhythms coordinate these primary rhythms by regulating melatonin levels and cerebral blood flow, while exercise patterns adjust GS function via aquaporin-4 (AQP4) polarization. Additionally, we elaborate on the cascade effect of AD resulting from rhythmic dysregulation. A thorough understanding of how rhythmic activities impact Aβ clearance by the GS may offer new perspectives and potential intervention strategies for the prevention and treatment of AD through the concept of "synchronized multiple rhythms"-a novel framework that integrates multi-rhythm synergy. Clinically, this work provides a theoretical basis for developing targeted interventions, such as personalized exercise timing regimens, respiratory rhythm training, and closed-loop neurovascular feedback devices, to restore GS function in AD patients.

RevDate: 2025-12-10

Du M, Li N, Li T, et al (2025)

Chimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates.

Nature communications pii:10.1038/s41467-025-67207-4 [Epub ahead of print].

While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and amyloid-β (Aβ). Notably, a single intravenous administration of blood brain barrier (BBB)-penetrating adeno-associated viral vector (AAV) encoding an Aβ-targeting FcRTAC construct achieves sustained therapeutic effects, establishing proof-of-concept for AAV-mediated delivery of an Aβ degrader as a strategy for Alzheimer's disease treatment. Our comprehensive investigation of binding properties of FcRTACs reveals critical molecular determinants of function and enables development of optimized engineering approaches. In summary, our approach represents a versatile therapeutic platform for treating diverse diseases ranging from autoimmune disorders to neurodegenerative conditions, while simultaneously serving as a user-friendly, plug-and-play research tool for extracellular protein knockout in basic biological research.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Kubohira Y, Okano N, Taharabaru T, et al (2026)

A water-soluble β-cyclodextrin polymer reduces cholesterol accumulation and autophagy dysfunction in vitro and in Niemann-Pick type C disease model mice.

Carbohydrate polymers, 374:124676.

Niemann-Pick disease type C (NPC) and Alzheimer's disease (AD) are characterised by cognitive dysfunction and neurological impairment. In both diseases, the abnormal accumulation and disruption of cholesterol homeostasis in the brain may contribute to the pathogenesis and exacerbation of symptoms. Cyclodextrins (CDs) are attracting attention as therapeutic agents that can reduce free cholesterol in the brain. A water-soluble β-CD polymer (β-CDP) consisting of multiple β-CDs cross-linked by epichlorohydrin was recently developed and reportedly has improved safety and higher circulation time in the bloodstream. In this study, we evaluated the potential of β-CDP as a promising therapeutic agent for NPC and AD. β-CDP lowered free cholesterol levels and reversed autophagy dysfunction in cholesterol-accumulated human neuroblastoma cells. Longer circulation time in the bloodstream and reduced cholesterol accumulation in NPC mice were also observed after its subcutaneous administration. These results suggest that β-CDP may be a safe therapeutic agent in the treatment of NPC and AD.

RevDate: 2025-12-10

Supasai S, Suntaratti P, Odton M, et al (2025)

HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl3/D-galactose rat model of Alzheimer's disease.

Experimental neurology pii:S0014-4886(25)00448-0 [Epub ahead of print].

Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1): a pivotal regulator of … HMGB1 Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl3 and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.

RevDate: 2025-12-10

Xu J, He Z, Pan Y, et al (2025)

Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.

Biomaterials advances, 181:214619 pii:S2772-9508(25)00446-7 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Hooshmandi E, Rafiei E, Owjfard M, et al (2025)

Neuroprotective and Immunomodulatory effects of human hair follicle stem cells on streptozotocin-induced memory impairment in rats: insights into inflammation and neurotrophic mechanisms.

Molecular biology reports, 53(1):178.

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD), a primary cause of dementia, involves cognitive decline and neuroinflammation. Human hair follicle stem cells (hHFSCs) have shown neuroprotective potential, but their effects on immune modulation, especially in xenogeneic transplantation, remain unclear. This study aimed to investigate the therapeutic potential of hHFSCs against memory impairment and neuroinflammation induced by streptozotocin (STZ) in male rats.

METHODS: Adult male Sprague-Dawley rats were intracerebroventricularly injected with STZ (3 mg/kg) to induce AD-like cognitive deficits. hHFSC transplantation (1 × 10[6]) was done on days 4, 14, and 21 post-surgery. Y-maze and Passive avoidance were used to assess memory. Hippocampal tissue was analyzed for mRNA expression of pro/anti-inflammatory factors and neurotrophic markers using quantitative RT-PCR. Histological evaluation quantified hippocampal pyramidal neurons and volume.

RESULTS: STZ significantly impaired memory in passive avoidance test, but not Y-maze. hHFSC significantly improved memory performance. mRNA analysis revealed elevated BDNF, TGFβ, and GFAP levels in the STZ group. The increased TGFβ and GFAP levels continued following hHFSC treatment, indicating a compensatory response. Moreover, pro-inflammatory factors (IL-1β, IL-6, and TNFα) were upregulated following hHFSC therapy, suggesting persistent neuroinflammation. hHFSC led to anti-inflammatory effects through the elevation of IL-10. In addition, hHFSCs significantly reduced hippocampal atrophy and neuronal loss induced by STZ.

CONCLUSION: hHFSCs exhibit partial neuroprotective effects against STZ-induced memory impairment. The simultaneous upregulation of pro- and anti-inflammatory markers underscores the complexity of the inflammatory response in this xenogeneic model. Future investigations should consider immunocompromised models or immunosuppressive protocols better to isolate the therapeutic effects of hHFSCs from immune responses.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Yu SP, Gu X, Jiang MQ, et al (2025)

Combined Preventive and Preconditioning Treatments for the Comorbidity of Alzheimer's Disease and Ischemic Stroke in a GluN3A Knockout Mouse and a 5xFAD Mouse.

Cells, 14(23): pii:cells14231871.

Alzheimer's disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5-2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke.

RevDate: 2025-12-10

He Q, Xia Y, Shen Q, et al (2025)

Relationships between sarcopenia and Alzheimer's disease: screening for mitochondria-related biomarkers.

Computer methods in biomechanics and biomedical engineering [Epub ahead of print].

This study aims to identify mitochondrial-related biomarkers for sarcopenia and Alzheimer's disease (AD). Through the GEO database and machine learning algorithms, three diagnostic biomarkers (FKBP5, PRKAG1, and FBP2) were identified, and the constructed models showed good diagnostic accuracy in both internal and external datasets. Furthermore, multiple analyses such as GSEA, immune infiltration, and drug prediction were conducted. These findings provide new insights into shared pathological mechanisms and clinical diagnosis and treatment of sarcopenia and AD. Further clinical and experimental studies are needed to validate these results.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Pang R, Jia Q, Ma C, et al (2025)

Alzheimer's Disease: The Current and Emerging Treatment Approaches.

Behavioural neurology, 2025:9627699.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) as its main pathological features. It mainly manifests as cognitive dysfunction, and its pathological process may occur before symptom onset. However, the current drugs and methods for treating AD have unsatisfactory therapeutic outcomes. Therefore, finding a treatment that can inhibit the progression of AD by targeting its pathological features is an urgent need. This review summarizes the current traditional drugs that can delay the progression of AD and new drugs that act on the pathological characteristics of AD and highlights the potential value of related plant extracts. In addition, this review explores the application of different vectors, such as viral vectors and nanoparticles, in gene therapy and drug delivery. These data will provide novel ideas for new drug development and the search for new therapeutic mechanisms.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Wang X, Yang F, Chen P, et al (2025)

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alzheimer's Disease: A Novel Cell-Free Therapeutic Strategy and Diagnostic Biomarker.

International journal of nanomedicine, 20:14375-14391.

With the ongoing trend of population aging worldwide, the incidence of Alzheimer's disease (AD) is steadily increasing. In the absence of effective therapeutic options for atypical forms of AD, reducing its prevalence and improving treatment outcomes have become pressing priorities. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have attracted growing attention as a new cell-free therapeutic approach for AD due to their high stability, low immunogenicity, and minimal tumorigenic risk. This review provides a comprehensive overview of the pathological mechanisms underlying AD, highlights the diagnostic potential of MSC-EVs, and elaborates on their therapeutic advantages and mechanisms of action. Furthermore, it addresses the key challenges and considerations associated with the clinical translation of MSC-EVs.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Toyli A, Shaik A, Zhao C, et al (2025)

The heart-brain axis: unraveling the interconnections between cardiovascular and Alzheimer's diseases.

Frontiers in cardiovascular medicine, 12:1685461.

Cardiovascular disease (CVD) and Alzheimer's disease (AD) are leading causes of death and disability worldwide, and recent research has increasingly illuminated a complex, bidirectional relationship between the two. This review synthesizes epidemiological, mechanistic, imaging, and genetic evidence linking CVD and AD through the heart-brain axis-a network of interrelated physiological and demographic pathways. We detail how cerebral hypoperfusion, inflammation, blood-brain barrier dysfunction, imbalance of the autonomic nervous system, and systemic amyloidosis contribute to shared neurodegenerative and cardiovascular outcomes. Multi-organ imaging studies, including MRI and PET, reveal that dysfunction of the cardiovascular system correlates with brain atrophy, white matter lesions, glymphatic impairment, and accumulation of AD-related proteinopathies. Genetic analyses further support overlapping risk architectures, particularly involving APOE and loci associated with lipid metabolism, vascular integrity, and inflammation. Age and sex are critical modifiers, with midlife CVD exerting the strongest influence on later cognitive decline, and sex-specific physiological responses shaping disease susceptibility. Finally, we explore how modifiable lifestyle factors, pharmacologic interventions, and precision medicine approaches targeting inflammatory and vascular pathways can jointly reduce the burden of both CVD and AD. Multidisciplinary collaboration to understand the interconnected biology of the heart and brain is essential for advancing integrated prevention and treatment strategies in aging populations.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Yang C, Li B, Yang S, et al (2025)

Electroacupuncture Prevents Against AD-Like Phenotypes in APP/PS1 Mice: Investigation of the Mechanisms From Cerebral Microangiopathy.

CNS neuroscience & therapeutics, 31(12):e70696.

BACKGROUND: Electroacupuncture (EA) has been widely used in Alzheimer's disease (AD) treatment. However, its underlying mechanisms remain poorly elucidated.

PURPOSE: This study aimed to investigate the effects of EA on AD-like phenotypes and explore the mechanisms.

METHODS: We first evaluated AD-like behaviors and cerebral blood flow (CBF) changes in APPswe/PS1dE9 (APP/PS1) mice at different ages. Subsequently, the therapeutic effects of EA at acupoints Baihui (GV20), Guanyuan (CV4), and Zusanli (ST36), as well as sunitinib, a PDGFRβ-specific inhibitor, on AD-like phenotypes in APP/PS1 mice were investigated. CBF was monitored by laser speckle imaging, and hippocampal synaptic ultrastructure and microvascular morphology were examined by transmission electron microscopy (TEM). Western blot was performed to measure related protein expression. Finally, functional ultrasound (fUS) imaging was used to assess changes in brain-wide functional connectivity.

RESULTS: Compared with age-matched wild-type (WT) mice, 6- and 9-month-old APP/PS1 mice exhibited significant cognitive decline, while all age groups (3-, 6-, and 9-month-old) of APP/PS1 mice showed significantly reduced CBF. APP/PS1 mice showed elevated expression of microvascular markers in both the hippocampus and cortex. EA significantly ameliorated AD-like behaviors and prevented CBF reduction as well as microvascular deformation in 6-month-old APP/PS1 mice compared with non-treatment group. TEM and western blot analysis revealed damaged synaptic structure and reduced synaptic proteins in APP/PS1 mice, all of which were markedly alleviated by EA treatment. In addition, EA treatment downregulated the aberrantly elevated expression of PDGFRβ and CD31, enhanced the levels of tight junction proteins (Occludin, Claudin-5, and ZO-1) and glucose transporter 1 (GLUT1), and suppressed the expression of inflammatory proteins. Of note, intervention with sunitinib also improved AD-like behaviors in APP/PS1 mice. Remarkably, fUS imaging results showed that EA enhanced the functional connection between hippocampal regions of APP/PS1 mice.

CONCLUSION: Our data demonstrates that EA ameliorates AD-like phenotypes, potentially through preventing microangiopathy.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Lin Z, Hong Y, Hu Y, et al (2025)

White matter hyperintensity modulates the amyloid-tau-cognition association and anti-amyloid treatment efficacy in asymptomatic older adults.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70990.

INTRODUCTION: White matter hyperintensities (WMH), a key imaging biomarker of small vessel injury, may play a complex role in Alzheimer's disease (AD). We hypothesize that WMH not only directly contributes to cognitive decline but also moderates the relationship among AD pathology, treatment, and cognitive decline.

METHODS: A total of 1169 participants with 240-week follow-up in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were analyzed. Linear regression models examined WMH's contribution to cognitive decline, its interaction with Aβ on p-Tau217 level, and its interaction with anti-amyloid treatment on cognitive decline.

RESULTS: Increase in WMH volume independently contributed to cognitive decline (p = 0.0028). Baseline WMH significantly moderated the relationship between Aβ change and p-Tau217 change (p = 0.0035). Specifically, Aβ accumulation correlated with p-Tau217 increase only in participants with low baseline WMH. WMH growth was associated with cognitive decline only in the treatment group (p < 0.0001).

DISCUSSION: WMH modulates the interplay of pathologies, emphasizing the need for comprehensive treatment approaches targeting multiple pathways.

HIGHLIGHTS: White matter hyperintensity (WMH) independently contributed to cognitive decline. WMH modulated the longitudinal relationship between Aβ and p-Tau217. WMH interacted with anti-amyloid treatment on longitudinal cognitive decline.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Moretti DV, Kuhn E, Dubbelman M, et al (2025)

Clinical definition, biological characterization, and detection guidelines of subjective cognitive decline due to Alzheimer's disease and related dementia: A position paper from ISTAART SCD PIA.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70847.

Subjective cognitive decline (SCD)-self-perceived cognitive worsening without objective deficits-has emerged as a clinically meaningful, potential early manifestation of Alzheimer's disease (AD). Positioned at the intersection of normal aging, neuropsychiatric symptoms, and preclinical neurodegeneration, SCD offers a unique window for early detection and intervention. However, detection heterogeneity, variable prognostic trajectories, and limited equity in assessment hinder its full clinical utility. This position paper synthesizes current evidence on SCD's diagnostic complexity, neurobiological underpinnings, and modifiable influences. We highlight the need for harmonized assessment frameworks, scalable digital tools, inclusive research, and ethically grounded biomarker disclosure practices. Importantly, we advocate for personalized, (non-)pharmacological interventions targeting this early phase. By refining the conceptualization and operationalization of SCD, we can better identify individuals at heightened AD risk and deliver timely, equitable, and meaningful prevention strategies. SCD represents a pivotal inflection point in the dementia continuum-and a call to shift toward proactive brain health. HIGHLIGHTS: Subjective cognitive decline (SCD) may signal early-stage Alzheimer's despite normal test performance. Diagnostic heterogeneity limits current clinical and research utility. Biomarkers and digital tools could enhance risk stratification in SCD. Mental health and social context shape symptom reporting and outcomes. SCD offers a window for tailored (non-drug) preventive interventions.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Feng Y, Wang S, Xia H, et al (2025)

Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.

Translational neurodegeneration, 14(1):65.

Advancements in visualization methods have brought the meningeal lymphatic system (MLS) into the spotlight. The meningeal lymphatic vessels (mLVs) play a vital role in draining cerebrospinal fluid and immune cells, acting as a central hub for immune surveillance in the brain. Age-related morphological and functional declines of mLVs suggest their involvement in the pathogenesis of neurodegenerative disorders (NDDs). In this article, we summarize key discoveries about the MLS over the past decade, highlight the neuro-immune crosstalk in the meninges, and discuss the role of mLVs in both brain homeostasis and neurodegeneration. As a critical regulator of brain function and a potential therapeutic target, the MLS offers a promising avenue for the diagnosis and treatment of NDDs, particularly Alzheimer's Disease.

RevDate: 2025-12-09
CmpDate: 2025-12-10

Lee WJ, Cho K, Lee D, et al (2025)

Therapeutic Efficacy of Autologous Blood-Derived Stem Cells with Growth Factors in Moderate to Severe Alzheimer's Disease: A Clinical Trial.

Molecular neurobiology, 63(1):277.

Alzheimer's disease (AD) is characterized by cognitive decline, memory loss, and a gradual loss of daily functioning. Unfortunately, despite extensive research, effective treatments for AD remain limited. Of these, stem cell-based therapies show promise for their regenerative potential and ability to modulate pathological processes. Autologous blood-derived stem cells (ABSCs), which are isolated from a patient's own blood, have demonstrated therapeutic efficacy in AD. This clinical study evaluated the safety and efficacy of ABSCs on patients with AD and investigated the changing levels of growth factors derived from ABSCs treatment. The efficacy of the treatment on cognitive function was assessed using the Mini-Mental State Examination, Clinical Dementia Rating, and AD Assessment Scale-Cognitive Subscale, all widely used tools to assess cognitive function in patients with AD. The neuroimaging and molecular mechanisms were the secondary outcomes. The neuroimaging examinations performed included PET-CT with amyloid imaging, for assessing amyloid plaque deposition in the brain at baseline and at 3 and 6 months after treatment; FDG-PET, for measuring brain glucose metabolism and acquiring insights into neuronal activity and overall brain function; and MRI, performed at baseline and follow-up, for assessing structural brain changes. ABSCs treatment resulted in notable improvements in cognitive function, reductions in amyloid plaque burden, and improved neuroimaging outcomes. Autologous stem cell therapy also reduced the risk of immune rejection, offering a safety advantage over allogeneic stem cell therapies. Furthermore, the use of growth factors to enhance stem cell efficacy aligns with existing research demonstrating improvements in stem cell limitations. This study provides compelling evidence that ABSCs combined with growth factors exhibit significant therapeutic potential for patients with moderate to severe AD. Our findings indicate that our current combination treatment may offer a multi-target approach to addressing the complex pathogenesis of neurodegenerative diseases and is thereby a potentially sustainable therapeutic strategy for AD. Furthermore, the combination of ABSCs with growth factors can potentially provide a much-needed therapeutic alternative for AD.

RevDate: 2025-12-09

Majumder M, Dutta D, Paidi RK, et al (2025)

Activation of PPARα by gemfibrozil lowers tau-associated neuropathology in the MAPT mouse model of Alzheimer's disease.

Brain research pii:S0006-8993(25)00652-3 [Epub ahead of print].

The current dogma states that inhibiting tau accumulation and its associated neuropathologies might be a relevant strategy to prevent neuronal loss and cognitive dysfunction in Alzheimer's disease (AD). The present study demonstrates the therapeutic potential of an FDA-approved lipid lowering drug and an agonist of peroxisome proliferator and activated receptor α (PPARα), called gemfibrozil, in reducing tau accumulation and associated neuropathologies in the MAPT (PS19) mouse model of AD, expressing P301S mutated form of human tau protein in neurons. Daily oral treatment of gemfibrozil in MAPT mice reduced total tau and phosphorylated form of tau in the hippocampal subregions including CA1 and DG. Concurrently, gemfibrozil treatment upregulated PPARα level in the hippocampus and that was accompanied with inhibition of microgliosis and astrogliosis. Gemfibrozil also attenuated the loss of synaptic plasticity as determined by the expression of post-synaptic protein, PSD95, and calcium influx in the hippocampal tissue. The instrumental role of PPARα in gemfibrozil-mediated reduction of tauopathy was confirmed as PPARα deficiency in MAPT mice significantly augmented tau and phospho-tau accumulation in the hippocampus and gemfibrozil treatment failed to reverse tau pathology and gliosis in the brain of PPARα deficient MAPT mice. Lastly, gemfibrozil improved the cognitive function of MAPT mice during the symptomatic phase of disease progression, but it failed to reverse cognitive impairment in the PPARα deficient MAPT mice. These data suggest that neuroprotective effects of gemfibrozil in MAPT mice is mediated by PPARα. Moreover, targeting PPARα by small molecules like gemfibrozil may hold translational potential against tauopathy.

RevDate: 2025-12-09

Zhang X, Yang J, Xiao M, et al (2025)

Yangxue Qingnao Wan ameliorates cognitive impairment in scopolamine-induced AD mice via modulating neuropeptide signaling pathways and suppressing neuroinflammation.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 150:157602 pii:S0944-7113(25)01237-1 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD), a fatal neurodegenerative disorder with increasing incidence worldwide, remains a significant therapeutic challenge. Yangxue Qingnao Wan (YXQNW), a traditional Chinese medicine, has shown promise in AD treatment. However, its intricate mechanism of action necessitates further investigation. Clarifying YXQNW's active components and molecular targets could advance novel therapeutic strategies for AD.

PURPOSE: This research aimed to identify anti-AD bioactive compounds in YXQNW and investigate their mechanisms using transcriptomic profiling and network proximity analysis.

METHODS: The neuroprotective effects of YXQNW were evaluated in scopolamine (SCOP)-induced AD mice through behavioral tests, histopathological assessments, and biochemical analyses (acetylcholinesterase activity, oxidative stress markers and pro-inflammatory cytokines). Transcriptomic analysis was employed to explore YXQNW's regulatory targets and pathways. Key targets were validated by RT-qPCR, immunofluorescence (IF) and Western blot. Network proximity was used to predict anti-AD components, followed by in vitro mechanism validation in SCOP-induced HT22 cells using Gpr139 agonist and antagonist.

RESULTS: YXQNW ameliorated spatial memory deficits, cholinergic dysfunction, oxidative stress, and neuroinflammation in vivo. Transcriptomics analysis uncovered significantly modulation of neuropeptide signaling pathways, including upregulation of Gpr139 and downregulation of Gal/Galr1, mitigating cognitive impairment. Network proximity identified 8 anti-AD components, with Palmatine, Ligustilide, and Obtusifolin demonstrating efficacy in reducing oxidative stress, inflammation, and neuronal damage in vitro, and could also regulate the expression of neuropeptides. Moreover, Palmatine inhibits neuroinflammation via regulating Gpr139 protein expression.

CONCLUSIONS: YXQNW alleviates AD-like pathology by restoring cholinergic homeostasis, suppressing oxidative stress and neuroinflammation, and regulating neuropeptide signaling. And its active ingredient (Palmatine) can inhibit inflammatory response by regulating the expression of Gpr139 protein. This study supports YXQNW's clinical application and provides novel insights for AD drug discovery.

RevDate: 2025-12-09

Taj T, Kaushik M, Islam A, et al (2025)

Microbiota-brain interaction: The role of gut-derived proteins in addressing various neurological disorders including Parkinson's (PD) and Alzheimer's diseases (AD).

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 193:118861 pii:S0753-3322(25)01055-8 [Epub ahead of print].

The microbiota-brain interaction is a complex network connecting gut microbiota to the enteric nervous system (ENS) and the central nervous system (CNS) that are crucial for neurotransmission and neurological health. Metabolites such as short-chain fatty acids (SCFA), neurotransmitters, and neuromodulators from the gut microbiota influence behavior and brain function. This review focuses on the study related with gut bacteria, including Bifidobacterium infantis and Lactobacillus species, producing various metabolites in gut including bile acids, SCFA, histamine, and others to communicate with the brain or CNS. Dysbiosis can lead to neurological conditions such as anxiety, depression, PD, and AD. SCFAs from gut bacteria bind to the free fatty acid receptors of intestinal epithelial cells (IECs), affecting neurones and influencing neuroactivity. Gut bacteria also produce neurotransmitters that regulate growth hormone release through interactions with the CNS and endocrine systems. Brain signals interact directly with the pituitary and adrenal glands through the hypothalamic-pituitary-adrenal (HPA) axis, which in turn communicates with enteroendocrine cells (EECs). Investigating probiotics, prebiotics, and dietary changes could open new avenues for treatment for mental and neurological problems.

RevDate: 2025-12-09

Shi Y, Zhang H, Cong S, et al (2025)

Benzylpiperidine-pyridazin-3(2H)-one derivatives as potential multifunctional agents against Alzheimer's disease.

European journal of medicinal chemistry, 303:118437 pii:S0223-5234(25)01202-4 [Epub ahead of print].

Based on multitarget-directed-ligands (MTDLs) strategy, a series of benzylpiperidine-pyridazin-3(2H)-ones were designed, synthesized and evaluated as innovative multifunctional agents for Alzheimer's disease (AD). Biological evaluation revealed that most compounds exhibited excellent acetylcholinesterase (AChE) inhibition, potent antioxidant activity and moderate β-amyloid (Aβ1-42) aggregation inhibition. Among them, compound 7a emerged as a synergistic multifunctional agent with significant inhibition of AChE (EeAChE: IC50 = 0.21 μM; HsAChE: IC50 = 13 nM) and anti-Aβ activity (IC50 = 2.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.28 μM for disaggregation of Aβ1-42 fibrils; IC50 = 3.72 μM for Cu[2+]-induced Aβ1-42 aggregation; IC50 = 2.16 μM for disaggregation of Cu[2+]-induced Aβ1-42 fibrils). In addition, 7a was endowed with the potential to serve as antioxidant (2.88 Trolox equivalents), metals chelator and anti-neuroinflammatory agent for synergistic treatment. Moreover, 7a exhibited pronounced neuroprotective effects across multiple cellular models. Pharmacokinetically, 7a displayed favorable brain penetration (AUCbrain/plasma = 0.77) and sustained exposure. In vivo evaluation demonstrated that 7a effectively ameliorated scopolamine-induced cognitive impairment in the Morris water maze, which was associated with restored cholinergic function and mitigated oxidative stress in mice. The synergistic multi-target efficacy combined with favorable pharmacokinetic properties underscores its potential as a disease-modifying therapeutic agent for AD.

RevDate: 2025-12-09

Kim SR, Kim SK, Kobayashi H, et al (2025)

Efficacy of MR Imaging Findings in Clinical Management of Hepatic Encephalopathy and Alzheimer's Disease.

Hepatology research : the official journal of the Japan Society of Hepatology [Epub ahead of print].

In the aging society, distinguishing hepatic encephalopathy (HE) from Alzheimer's disease (AD) poses significant clinical challenges attributed to overlapping neuropsychiatric symptoms including memory loss, disorientation, and impaired daily functioning. Traditional diagnostic approaches relying on clinical assessment and biochemical markers often prove insufficient, necessitating advanced neuroimaging techniques for differential diagnosis. This review examines magnetic resonance imaging (MRI) techniques for differential diagnosis of HE and AD, focusing on T1-weighted imaging findings characteristic of HE, and voxel-based specific regional analysis system (VSRAD) applications in AD diagnosis. Analysis of the literature encompassed peer-reviewed articles examining neuroimaging patterns, diagnostic accuracy, and clinical correlations in both HE and AD. T1-weighted MRI displays bilateral symmetric hyperintensity at the globus pallidus in 70%-90% of HE patients attributed to manganese deposition secondary to impaired hepatic clearance, and provides evidence of HE-related brain changes independent of ammonia levels. VSRAD analysis reveals characteristic medial temporal lobe atrophy patterns in AD, with diagnostic accuracy rates of 91.6% for very mild, 95.8% for mild, and 98.2% for moderate-to-severe AD. Clinical studies demonstrate that brain atrophy detected by VSRAD correlates significantly with functional impairment in activities of daily living, independent of conventional liver function parameters. The integration of T1-weighted MRI and VSRAD analysis provides enhanced diagnostic accuracy for differentiating HE-associated cognitive impairment from primary neurodegenerative conditions, offering valuable prognostic information regarding functional capacity and cognitive trajectory. This systematic neuroimaging approach enables more precise therapeutic decision-making, signals treatment expectations, and directs rehabilitation planning and long-term care strategies in an aging population with increasing prevalence of both hepatic and neurodegenerative disorders.

RevDate: 2025-12-09

Nakamura Y, Kurokawa T, Terashima S, et al (2025)

Efficacy and safety of a novel, extended-release rivastigmine transdermal patch (TW-4752N) in patients with Alzheimer's disease: A 24-week randomized, double-blind trial with a 28-week open-label extension.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundRivastigmine may offer greater efficacy and convenience of use with a novel formulation than previously reported.ObjectiveTo evaluate the efficacy and safety of a novel, twice-weekly rivastigmine patch (TW-4752N) (TW) in Alzheimer's disease (AD) patients with mild to moderate dementia.MethodsThis was a multicenter, phase III, double-blind study comparing TW and an existing rivastigmine transdermal patch (RT) with an open-label extension. The primary endpoint was the change in ADAS-Jcog total score at week 24 from baseline. Secondary endpoints included the ADAS-Jcog total score at weeks 8, 16, and 24.ResultsA total of 354 and 362 patients were available for efficacy and safety analysis, respectively. Changes in ADAS-Jcog total score at week 24 from baseline were similar between the two groups in the full analysis set with an intergroup difference of -0.84 ± 0.44 (95% CI, -1.695 to 0.016) and with the upper limit of the 95% CI being below the non-inferiority margin of 1.1, demonstrating the non-inferiority of TW. However, analysis of the per-protocol set demonstrated a significant intergroup difference in favor of TW likely suggesting a greater treatment effect with TW than with RT (p = 0.032). Adverse events (AEs) reported in ≥3% of patients were similar between the groups, with the only AE with an intergroup difference of ≥10% in incidence being application site pruritus (TW/RT, 27.6%/17.1%).ConclusionsTW represents a viable alternative option of interest to patients with AD, providing comparable or potentially greater efficacy than RT and comparable safety, as well as greater convenience of use.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Burd SG, Bogolepova AN, Lebedeva AV, et al (2025)

[Epileptic seizures in patients with Alzheimer's disease].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 125(11):36-43.

Neurodegenerative diseases are one of the leading causes of epileptic seizures with onset in later life. Particular attention is paid to Alzheimer's disease (AD), as a disease that accounts for up to 70% of cases of all types of dementia, and, according to the literature, shares genetic and pathophysiological mechanisms with epilepsy. This paper reviews the literature on the prevalence of epilepsy in AD patients. The reasons for the widely varying data (ranging from 0.5 to 64%) depending on the selected population, the reliability of the established diagnosis, the form and genetic characteristics of the disease, as well as the examination methods used, are considered. The main risk factors for the development of AD and epilepsy, semiotics and features of seizures in patients with AD, as well as approaches to the treatment of such patients, are also covered.

RevDate: 2025-12-09

Jafari EA, Alshahawey M, Zaman MA, et al (2025)

Characterizing Alzheimer's Disease and Related Dementia in a Hypertension Population Within the State of Florida Using Electronic Health Record-Based Data.

Clinical pharmacology and therapeutics [Epub ahead of print].

Hypertension is a known modifiable risk factor for Alzheimer's disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013-12/31/2016), to identify apparent treatment-resistant hypertension (aTRH), and hypertension-control levels (well-controlled hypertension, intermediate-controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD-9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson-Aalen estimator and log-rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234-1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time (P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837-0.956) and fixed-dose combination medications (OR: 0.804, 95% CI: 0.732-0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.

RevDate: 2025-12-08

Li G, Li P, Huang L, et al (2025)

[Protective effects of quercetin, the key component of Zuo Gui Wan, against Alzheimer's disease via the PI3K/AKT pathway: insights from network pharmacology, molecular docking, and cell experiments].

Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences [Epub ahead of print].

OBJECTIVES: To investigate the protective mechanism of quercetin, the core component of Zuo Gui Wan, against Alzheimer's disease through the PI3K/AKT signaling pathway, based on network pharmacology, molecular docking, and cell experi-ments.

METHODS: The active components of Zuo Gui Wan were identified by searching TCMSP, PubChem, Swiss Target Prediction, and BATMAN-TCM databases, and their potential targets were predicted. The target information was standardized using Uniprot, and Alzheimer's disease-related target genes were obtained from Drugbank, GeneCards, and OMIM. The intersection of these datasets was used to identify the potential targets of Zuo Gui Wan for treating Alzheimer's disease. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of potential targets was visualized using Cytoscape 3.10.1 software and the STRING database. The key active compounds and core potential targets for treating Alzheimer's disease with Zuo Gui Wan were identified through calculation. Based on the enrichment analysis results and literature, quercetin and the PI3K/AKT pathway were selected for verification. Molecular docking and binding ability prediction between quercetin and the core target AKT were performed using CB-Dock2, and visualization was conducted with AutoDock and PyMOL software. Finally, Aβ1-42-induced HT-22 mouse hippocampal neuronal cells were used to construct an Alzheimer's disease cell model. Quercetin, the PI3K inhibitor LY294002, and the activator EGF were used as interventions. The groups were divided as follows: Control, Aβ1-42, Aβ1-42+Quercetin 2.5 μM, Aβ1-42+Quercetin 5 μM, Aβ1-42+Quercetin 10 μM, Aβ1-42+EGF, and the PI3K/AKT modulation group: Control, LY294002, LY294002+Quercetin 10 μM, LY294002+EGF. CCK-8 assays were performed to detect cell viability, while JC-1, Calcein AM-PI, and Hoechst staining were used to assess cell apoptosis. Western blotting was employed to detect the expression of relevant target proteins.

RESULTS: Network pharmacology and cell experiments collectively demonstrate that the key active ingredient of Zuo Gui Wan, quercetin, targets core proteins such as AKT1 and GSK3β through a network-based approach, significantly enriching the PI3K/AKT pathway. Molecular docking results indicate that quercetin has a strong binding affinity with AKT. Experimental validation in the Aβ1-42 oligomer-induced HT-22 model reveals that quercetin significantly activates the PI3K/AKT signaling pathway, which is inhibited by Aβ1-42 oligomers, as well as Bcl-2 protein expression. It also suppresses the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. JC-1, Hoechst 33342, and Calcein AM-PI staining results further show that quercetin can significantly alleviate apoptosis induced by Aβ1-42 oligomers in HT-22 cells. Treatment with the PI3K inhibitor LY294002 in HT-22 cells leads to reduced cell viability and decreased expression of p-AKT/AKT and Bcl-2 proteins, while increasing the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. Additionally, apoptosis levels increase as observed in JC-1, Hoechst 33342, and Calcein AM-PI staining, all of which can be reversed by quercetin and the PI3K agonist EGF.

CONCLUSIONS: Quercetin, the key active ingredient of Zuo Gui Wan, exerts its protective effects against Alzheimer's disease by regulating the PI3K/AKT signaling pathway, inhibiting neuronal cell damage and apoptosis.

RevDate: 2025-12-08
CmpDate: 2025-12-08

Menczel Schrire Z, Mitchell HF, Low LF, et al (2025)

NeuroMusic: protocol for a randomised-controlled trial of keyboard and singing music training programmes for older adults with mild cognitive impairment.

BMJ open, 15(12):e104158 pii:bmjopen-2025-104158.

INTRODUCTION: Music-based training programmes, such as learning how to play an instrument or sing in a choir, have been suggested as potential interventions for promoting healthy brain ageing in older adults at risk of cognitive decline because of their ability to enhance cognitive functions and potentially promote neuroplasticity. However, there is limited empirical evidence in older adults at risk of dementia, especially that evaluates both piano and singing interventions and their effects on cognition and neuroplasticity. In this protocol, we outline a study to assess the efficacy of keyboard and singing music training programmes on reducing cognitive decline and other outcomes in older adults with Mild Cognitive Impairment (MCI).

METHODS AND ANALYSIS: This randomised, single-blind, controlled, parallel-group trial aims to enrol 432 individuals with MCI from the community in Sydney, Australia. Participants are randomly allocated to participate in either keyboard lessons, singing lessons or a film discussion control group once a week for 3 months. The primary objective is to assess the effectiveness of two music training programmes (keyboard and choral singing) for enhancing verbal memory after 3 months compared with control. Additionally, we will examine how these music-based interventions affect other aspects of cognition, mood, sleep, overall well-being, markers of brain plasticity and blood biomarkers of Alzheimer's disease and neurodegeneration. Tertiary objectives are to identify factors that impact the success of the interventions, such as participation rates, engagement levels and key demographic and clinical features. Outcomes are collected at baseline and at 3 and 9 months. The primary endpoint analysis will include all randomised participants to estimate the treatment effect using intention-to-treat principles. Primary and secondary outcomes will be analysed using linear mixed models and effect size measures will be calculated.This study will be the first robust, randomised controlled trial to assess the potential and relative value of music engagement for cognitive decline in high-risk MCI individuals, as well as broader effects on other markers of mental health, well-being and neurodegeneration. Co-designed with implementation in mind, the music interventions can potentially be delivered within memory clinic or community settings.

ETHICS AND DISSEMINATION: The Sydney University Human Research Ethics Committee (2023-026) has approved this protocol. The trial findings will be shared through conferences, publications and media.

TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12623000407695), Registered 21/04/2023 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385552 PROTOCOL VERSION: 2.02 29/11/2024.

RevDate: 2025-12-08

Pan L, Song X, Su G, et al (2025)

N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor.

Journal of the American Chemical Society [Epub ahead of print].

Heparan sulfate (HS) plays a central role in signal transduction, while Reelin is an essential signaling protein in both the developing and adult brain. A Reelin COLBOS variant was recently discovered with enhanced HS binding and resilience against autosomal dominant Alzheimer's disease (ADAD), underscoring the importance of Reelin-HS interactions. However, the glycan determinants of Reelin-HS interactions have not been well-characterized, which we systematically investigated here. Surface plasmon resonance (SPR) showed that full length Reelin binds HS with high affinity (KD = 17 ± 5 nM), which is enhanced by the COLBOS variant (KD = 10 ± 2 nM). Competition SPR and glycan array studies further revealed that HS N-sulfation is critical for Reelin-HS binding, consistent with Haddock modeling. In cell surface binding assays, heparinase treatment, which degrades HS, or the knockout of a key HS N-sulfation enzyme (NDST1) significantly reduced Reelin attachment. Functionally, a cellular split-luciferase assay showed that heparinase treatment or adding heparin in culture medium reduces Reelin-induced ApoER2 dimerization, demonstrating that HS is a coreceptor for Reelin receptor activation. In contrast, N-desulfated heparin does not inhibit Reelin receptor dimerization. Our work establishes HS as a coreceptor for Reelin signaling and N-sulfation as a key glycan determinant of Reelin-HS recognition. Our work provides mechanistic insights into diverse neurodevelopmental and neurodegenerative diseases associated with Reelin signaling and suggests novel therapeutic strategies targeting HS sulfation.

RevDate: 2025-12-09
CmpDate: 2025-12-09

Aggarwal G, Salas J, Vellas B, et al (2025)

High circulating adropin levels predict long-term blood pressure variability in old adults: evidence from the Multidomain Alzheimer Prevention Trial.

American journal of physiology. Heart and circulatory physiology, 329(6):H1684-H1692.

Hypertension and elevated visit-to-visit variability in blood pressure (BP) increase the lifetime risk of cardiovascular, kidney, and neurodegenerative diseases. Adropin, a hepatokine with autocrine/paracrine actions, contributes to cardiometabolic cross talk and mediates cellular stress responses across metabolic and cardiovascular tissues. Human cross-sectional and exercise studies suggest links between adropin, endothelial function, and vascular elasticity. Whether circulating adropin levels reflect risk of poor BP control remains unclear. We examined relationships between plasma adropin concentrations, BP, and visit-to-visit BP variability in older, community-dwelling participants from the Multidomain Alzheimer Prevention Trial (MAPT: n = 443; means ± SD age, 75.9 ± 4.5 yr; 60% female). BP and heart rate while in the supine position were assessed every 6 mo for 5 yr (8.1 ± 1.3 measurements/participant). Multivariate regression modeling revealed a positive association between adropin and variation independent of the mean (VIM) in systolic BP (R = 0.329, F7,429 = 7.454, P < 0.001). Predictors included adropin (β = 0.165, P < 0.001), age (β = 0.146, P < 0.005), sex (male = 1, female = 0; β = -0.130, P = 0.005), and antihypertensive medication use (yes = 1, no = 0; β = 0.188, P < 0.001). Stratification by medication use suggested that the association between adropin and systolic BP VIM is confined to participants on antihypertensive therapy (R = 0.347, F6,188 = 4.302, P < 0.001; adropin, β = 0.233, P = 0.001). However, analysis by grouping participants in tertiles ranked by adropin or systolic BP VIM suggests that, although the relationship is notably weaker, it is not absent for participants not on antihypertensive medications. In conclusion, elevated plasma adropin concentrations associate with systolic BP variability in older adults with hypertension. These findings identify adropin as a potential biomarker of poor BP control.NEW & NOTEWORTHY This study identifies circulating levels of the hepatokine adropin as a novel biomarker of blood pressure (BP) variability in older adults. Using longitudinal data from the Multidomain Alzheimer Prevention Trial, we show that higher adropin levels predict greater systolic BP variability, particularly in participants receiving antihypertensive therapy. These findings link a hepatokine with cardiovascular risk and suggest that adropin measurement may improve stratification of individuals at risk for poor BP control and treatment resistance.

RevDate: 2025-12-09

Anonymous (2025)

Erratum.

Neuro-degenerative diseases, 25(4):228.